A common problem with the administration of many pharmaceutical compounds, including therapeutic and diagnostic drugs, has been the need to retain effective quantities of these compounds in contact with targeted tissue sites for sufficient periods of time to accomplish the desired therapeutic or diagnostic purpose. This problem is particularly acute in connection with physiological systems characterized by rapid fluid turnover or drainage. For example, in the ocular environment tear turnover and drainage through the lacrimal drainage system quickly remove the major portion of any pharmaceutical compound administered to the surface of the eye so that only a small fraction of the original dosage remains in contact with the ocular tissue for any period of time. Analogous problems are encountered in connection with the treatment of the nasal mucosa, oral and anal cavities, uro-genital track, vagina and similar physiologic environments.
Early approaches at addressing this problem generally relied upon the repeated administration of relatively large dosages of pharmaceutical compounds to compensate for the rapid loss of the compounds following their administration to the target site. Though relatively successful at maintaining effective concentrations of the desired pharmaceutical agents in contact with the target tissue such strategies were wasteful and had a number of drawbacks. These drawbacks included the expense associated with using relatively large quantities of pharmaceutical compounds, patient discomfort with repeated drug administration and systemic side-effects associated with large and frequent drug doses. Alternative approaches to the solution of this problem utilized viscous ointments and gels as delivery vehicles for the pharmaceutical compounds. These semi-solid delivery vehicles slowed down the rapid loss of the pharmaceutical compounds and retained an adequate dosage in contact with the target tissue. However, effectively delivering a controlled drug dosage with such widely variable systems proved difficult. Additionally, though satisfactory for direct topical application to mucous membranes, skin and the conjunctiva of the eye, such viscous delivery vehicles were not suitable for injection. More over, when utilized to treat ocular conditions such drug containing ointments and gels formed barriers to sight and produced an uncomfortable and aesthetically unpleasant crusting along the edges of the eyelids. These drawbacks as well as the possibility of blockage of the lacrimal duct when used to treat the eye lead to decreased patient acceptability and utilization of these systems.
A more modern approach directed at overcoming these problems has been the use of controlled or sustained release drug delivery systems. Typically, these systems utilize a polymeric matrix incorporating a therapeutic or diagnostic pharmaceutical compound. The polymer matrix is usually configured as a macroscopic insert designed to be placed in contact with the target tissue site. Once in position, the incorporated pharmaceutical compounds are released in a controlled manner through diffusion from the polymer matrix or in response to erosion of the polymer through mechanical or chemical means. Though generally effective, a significant disadvantage associated with such macroscopic controlled release inserts was the need for medical personnel to position and remove the devices. Additionally, patient discomfort with the inserted devices limited their use.
The subsequent development of microparticulate polymeric drug delivery vehicles addressed some of these problems. Once suspended in solutions of appropriate viscosities they were capable of either topical administration or administration through injection. Additionally, when properly formulated patients were able to self-administer such microparticulate suspensions in the form of drops or ointments. However, in spite of these successes significant problems remain with the administration and handling of microparticulate drug delivery vehicles. For example, fluid turnover or drainage at the target site may prematurely sweep the microparticulates from the target tissue along with the carrier liquid. This problem is particularly acute when microparticulate suspensions are administered as eye drops.
Further detracting from their utility, microparticulate drug delivery vehicles formed from water labile polymers must be stored in an anhydrous environment until just prior to use. Unless a liquid carrier other than water is used to suspend such microparticulates, the end user must suffer the inconvenience of combining the aqueous liquid carrier with the microparticulates immediately prior to administration. Though water labile erodible polymer microparticulates may be preferred because they do not require removal from the target site following administration, their inability to remain suspended in a ready-to-use formulation makes it virtually impossible to provide a pre-mixed water labile microparticulate drug delivery vehicle with even a minute shelf life.
Further compounding these problems, the therapeutic and diagnostic compounds that typically would be incorporated into such microparticulate delivery vehicles are often hydrophilic, water soluble, or even water reactive. As a result, during storage in aqueous suspension these pharmaceutical compounds will leach from the microparticulate carriers into the carrier solution where they may react with solvent molecules. This may result in a substantial loss of the desired pharmaceutical activity as well as directly impacting the ability to control the drug delivery rate from the suspension. Thus, depending upon the diffusion rate of the hydrophilic, water soluble or water reactive pharmaceutical compound involved, the available shelf life of a microparticulate suspension will be much shorter than even the minimum desirable shelf life.
In addition to the problems of shelf life and longterm storage instability, when hydrophilic, water soluble or water reactive pharmaceutical compounds are incorporated into polymeric drug delivery vehicles there is a significant problem in maintaining control of the actual drug delivery characteristics such as the drug release rate and the drug delivery duration. Undesirably fast delivery rates can result from a variety of factors including the extent of drug loading within the polymer matrix, polymer swelling, diffusion rate and erosion rate as well as the length of time the polymer has remained in suspension prior to administration at the target site. Premature delivery also decreases the duration of drug availability.
An alternative drug delivery suspension is disclosed in U.S. Pat. No. 4,911,920. This patent discloses a sustained release ophthalmic formulation for treating glaucoma without the unpleasant stinging sensation normally associated with compounds for lowering intraocular pressure. The disclosed formulation incorporates an active pharmaceutical compound held in suspension by a cationic exchange resin dispersed in an aqueous solution or gel of an anionic polymer. The formulation is compounded by dispersing the cationic exchange resin in water, adding the active component and then the anionic polymer. When administered to the eye as a pourable liquid, gel or salt the active ingredient held by the cationic exchange resin and the anionic polymer is released when the ions naturally present in the tear fluid compete with the bound active ingredient for sites on the polymer vehicle and ionic exchange resin.
While reportedly effective at reducing ocular discomfort, this formulation does not address the problems of shelf life and long-term storage stability. More specifically, because the molecules of the active component or drug are free to defuse in and out of the ion exchange resin while maintaining an equilibrium concentration in the aqueous medium they are subject to degradation. This particularly true with respect to water labile compounds. Moreover, the release characteristics of this drug delivery vehicle may be less than desirable in that substantially spontaneous dumping of the bound active ingredient may occur at the target site. Additionally, when formulated at sufficient viscosities to reduce losses through drainage and turnover the compounds may interfere with vision.
Accordingly, it is principal object of the present invention to provide a sustained release pharmaceutical drug delivery composition having improved delivery characteristics and enhanced long-term storage stability.
It is an additional object of the present invention to provide a pharmaceutical drug delivery composition that is particularly well suited for use with hydrophilic, water soluble or water reactive pharmaceutical compounds and which may be formulated as an aqueous suspension that can be stored for a significant period of time prior to use.
It is a further object of the present invention to provide a sustained release pharmaceutical drug delivery composition with bioadhesive properties which enhance its retention at the target site without significantly increasing its viscosity.